The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

• Published in: Cell reports (Cambridge) 2017-06, Vol.19 (11), p.2304-2318
• Main Authors: Ignatius, Myron S., Hayes, Madeline N., Lobbardi, Riadh, Chen, Eleanor Y., McCarthy, Karin M., Sreenivas, Prethish, Motala, Zainab, Durbin, Adam D., Molodtsov, Aleksey, Reeder, Sophia, Jin, Alexander, Sindiri, Sivasish, Beleyea, Brian C., Bhere, Deepak, Alexander, Matthew S., Shah, Khalid, Keller, Charles, Linardic, Corinne M., Nielsen, Petur G., Malkin, David, Khan, Javed, Langenau, David M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; de-differentiation; Humans; MEF2 Transcription Factors - metabolism; MEF2C; muscle; NOTCH1; Receptor, Notch1 - metabolism; rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal - metabolism; Rhabdomyosarcoma, Embryonal - pathology; self-renewal; Signal Transduction; SNAI1; Snail Family Transcription Factors - metabolism; Transcription Factors - metabolism; tumor propagating cells; Xenopus Proteins - metabolism; Zebrafish
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.05.061

Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)—a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future. [Display omitted] •NOTCH1 expands the number of tumor-propagating cells (TPCs) in zebrafish and human ERMS•Notch1 drives the de-differentiation of zebrafish ERMS cells into self-renewing TPCs•A NOTCH1/SNAI1 pathway drives self-renewal and blocks MEF2C regulated differentiation•Self-renewal and differentiation pathways are linked and viable therapeutic targets Tumor-propagating cells (TPCs) drive cancer growth, yet mechanisms regulating TPC self-renewal and maintenance are largely unknown. Ignatius et al. show that the NOTCH1/SNAIL1 pathway synergizes with RAS to expand TPCs in embryonal rhabdomyosarcoma. This pathway blocks MEF2C-induced differentiation and enables the de-differentiation of ERMS cells into self-renewing TPCs.